Direct NMR screening of natural products obtained from hot water extracts of medicinal species is accomplished through STD and tr-NOESY experiments on a crude mixture and a given protein receptor. It is shown, with use of a mushroom extract as model case, that this protocol may provide a fast and simple method, particularly useful in natural products chemistry, through which to detect the presence of ligands for a target receptor. © Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.